RNU4-2 monoallelic variants as a leading cause of syndromic neurodevelopmental disorder, including in patients with parental consanguinity.

We analysed rare variants in the non-coding RNU4-2 gene as a potential cause of neurodevelopmental disorder (NDD) and intellectual disability (ID) in a large cohort of individuals enriched for parental consanguinity.Genome sequencing (GS) data from 22 928 individuals in our Biodatabank were queried for rare, monoallelic variants in RNU4-2 From these, 4918 patients presented with NDD/ID. Human Phenotype Ontology (HPO)-encoded clinical information was extracted and analysed using the ontologyX R package.Nearly 50% of the 4918 patients with NDD/ID reported parental consanguinity. Eight relevant heterozygous RNU4-2 variants were identified in 28 patients. n.64_65insT was the most frequently detected variant (20 patients, 71%), while the remaining variants were found in 1 or 2 patients each (n.65A>G, n.66A>G, n.67A>G, n.70T>C, n.76C>T, n.95C>G and n.135A>C). Four variants are novel or ultra-rare, and two of them are in the 3' stem loops. HPO-based analysis revealed a consistent syndromic phenotype characterised by NDD, abnormal brain morphology, hypotonia, global developmental delay, microcephaly, seizures, atypical behaviour and facial dysmorphism. RNU4-2 variants accounted for approximately 0.55% of NDD/ID cases in our full cohort, and 0.25% in the subset of consanguineous patients (all genetic causes included).This study underscores the significance of RNU4-2 as a major genetic cause of NDD/ID, extending its relevance to consanguineous patients, where recessive disorders are often suspected. We advocate for the re-evaluation of existing GS data to uncover potential diagnoses and emphasise the importance of GS as a first-tier diagnostic test.